Prodrug comprising beta-keto carboxylic acid, beta-keto carboxylic acid salt or beta-keto carboxylic acid ester for drug delivery

Abstract

There is provided a prodrug of a pharmaceutically active agent, such prodrug comprising a beta-keto carboxylic acid, a beta-keto carboxylic acid salt or a beta-keto carboxylic acid ester functional group, a pharmaceutical composition comprising the prodrug, and to the use of the prodrug or composition for treatment of a mammalian subject suffering from a condition which can be cured or alleviated by administration of the pharmaceutically active agent. There is further provided a method of inhibiting decarboxylation of a compound comprising a beta-keto carboxylic acid or a salt thereof with a monovalent cation, characterized in that a dry salt of the beta-keto carboxylic acid with a divalent or polyvalent cation is prepared.

1 - 35 . (canceled) 
     
     
         36 . A prodrug having the general formula (I): 
       
         
           
           
               
               
           
         
         represents a residue of a pharmaceutically active agent having the general formula 
       
       
         
           
           
               
               
           
         
         represents —COOH, a salt of —COOH with a physiologically acceptable cation, or an ester of —COOH, 
         for use in therapy. 
       
     
     
         37 . A prodrug according to  claim 36 , wherein formula (I″) represents —COOH or a salt of —COOH with a physiologically acceptable cation. 
     
     
         38 . A prodrug according to  claim 37 , wherein formula (I″) represents a salt of —COOH with a physiologically acceptable cation and said cation is Ca 2+  or Mg 2+ . 
     
     
         39 . A prodrug according to  claim 36 , wherein said prodrug is in dry solid form. 
     
     
         40 . A prodrug according to  claim 36 , wherein said pharmaceutically active agent in its conventional form has a solubility of less than 10 mg/ml in water at 25° C. 
     
     
         41 . A prodrug according to  claim 36 , wherein said pharmaceutically active agent, when administered in its conventional form, usually requires administration 2 or more times daily in order to maintain a therapeutically effective amount of the agent in the subject. 
     
     
         42 . A prodrug according to  claim 36 , wherein said pharmaceutically active agent is selected from the group consisting of Alclometasone, Alprostadil, Beclometasone, Betamethasone, Boceprevir, Budesonide, Bupropion, Camphor, Clarithromycine, Clobetasol, Clobetasone, Cortisone, Cyproterone, Daunomycin, Desonide, Desoximetasone, Dexamethasone, Dinoprostone, Docetaxel, Donepezil, Doxorubicin, Droperidol, Dydrogesterone, Ebastine, Epirubicin, Equilin, Erythromycin, Estrone, Etonogestrel, Everolimus, Exemestane, Fludrocortisone, Flumetasone, Fluocinolone acetonide, Fluprednidene, Gemeprost, Haloperidol, Hydrocortisone, Hydromorphone, Idarubicin, Ketamine, Ketobemidone, Ketotifen, Levo Norgestrel, Lofepramine, Medroxyprogesterone, Megestrol, Melperone, Methadone, Methylprednisolone, Mifepristone, Misoprostol, Mometasone, Nabumetone, Naloxone, Naltrexone, Nandrolone, Nomegestrol, Norethisterone, Ondansetron, Oxcarbazepine, Oxycodone, Paclitaxel, Patupilone, Pentoxifylline, Prednisolone, Prednisone, Progesterone, Propafenone, Propiomazine, Quinupristine, Rimexolone, Sirolimus, Sitaxentan, Spironolactone, Tacrolimus, Testosterone, Tibolone, Triamcinolone, Trimegestone, and Warfarin. 
     
     
         43 . A prodrug according to  claim 36 , wherein said pharmaceutically active agent is selected from the group consisting of Alclometasone, Camphor, Clarithromycine, Clobetasone, Cyproterone, Daunomycin, Desoximetasone, Droperidol, Dydrogesterone, Ebastine, Erythromycin, Haloperidol, Idarubicin, Ketobemidone, Medroxyprogesterone, Megestrol, Melperone, Methadone, Nabumetone, Pentoxifylline, Progesterone, Propafenone, Propiomazine, Rimexolone, Sirolimus, Tacrolimus, Warfarin, Boceprevir, Everolimus, Patupilone, and Sitaxentan. 
     
     
         44 . A prodrug according to  claim 36 , wherein said pharmaceutically active agent is selected from the group consisting of Alclometasone, Camphor, Clarithromycine, Clobetasone, Cyproterone, Daunomycin, Desoximetasone, Droperidol, Dydrogesterone, Ebastine, Erythromycin, Haloperidol, Idarubicin, Ketobemidone, Medroxyprogesterone, Megestrol, Melperone, Methadone, Nabumetone, Pentoxifylline, Progesterone, Propafenone, Propiomazine, Rimexolone, Sirolimus, Tacrolimus, and Warfarin. 
     
     
         45 . A prodrug according to  claim 36 , wherein said pharmaceutically active agent is selected from the group consisting of Alclometasone, Camphor, Clobetasone, Cyproterone, Daunomycin, Desoximetasone, Droperidol, Dydrogesterone, Ebastine, Haloperidol, Idarubicin, Ketobemidone, Medroxyprogesterone, Megestrol, Melperone, Methadone, Nabumetone, Pentoxifylline, Progesterone, Propafenone, Propiomazine, Rimexolone, Tacrolimus, and Warfarin. 
     
     
         46 . A prodrug according to  claim 36 , wherein said pharmaceutically active agent is Nabumetone. 
     
     
         47 . A pharmaceutical composition comprising a prodrug according to  claim 36 , and a pharmaceutically acceptable carrier. 
     
     
         48 . A pharmaceutical composition according to  claim 47 , further comprising said pharmaceutically active agent or a second pharmaceutically active agent having the same or similar therapeutic effect as said pharmaceutically active agent. 
     
     
         49 . A prodrug according to  claim 36 , for treatment of a mammalian subject suffering from a condition which can be cured or alleviated by administration of said pharmaceutically active agent. 
     
     
         50 . A method for the treatment of a mammalian subject comprising administering an effective amount of a prodrug according to  claim 36  to treat a condition which can be cured or alleviated by such administration. 
     
     
         51 . A method for the treatment of a mammalian subject comprising administering an effective amount of a prodrug according to  claim 37  to treat a condition which can be cured or alleviated by such administration. 
     
     
         52 . Method of inhibiting decarboxylation of a compound comprising a beta-keto carboxylic acid or a salt thereof with a monovalent cation, characterized in that a dry salt of said beta-keto carboxylic acid with a divalent or polyvalent cation is prepared. 
     
     
         53 . Method according to  claim 52 , wherein said divalent or polyvalent cation is a divalent metal cation. 
     
     
         54 . Method according to  claim 53 , wherein said divalent or polyvalent cation is Ca 2+ , Mg 2+ , Zn 2+  or Fe 2+ . 
     
     
         55 . Method according to  claim 54 , wherein said divalent or polyvalent cation is Ca 2+ .